The present invention generally relates to apparatus used for delivering medicinal fluid to a patient, and a method for fabricating such apparatus, and more specifically, to apparatus having an array of microneedles for transdermally delivering a medicinal fluid to a patient in a minimally invasive manner, and a method for fabricating the same.
There are many medical conditions and procedures in which it is necessary to either deliver a drug to a patient across the dermal barrier, or to withdraw a sample of blood or tissue from a patient across the dermal barrier. A hypodermic needle-tipped syringe is most commonly employed for transcutaneously delivering a medicinal fluid to a patient. A significant segment of the population considers receiving an injection delivered with a hypodermic needle to be a painful and unpleasant experience. Although most individuals are required to receive such injections only a few times over the course of their lifetime, those suffering from medical conditions such as diabetes will require much more frequent injections.
The size of the needle used with common hypodermic syringes is typically a few millimeters in length. These needles, which are referred to as macro-needles, have a relatively large diameter compared to the size of a biological cell. The pain associated with a needle piercing a dermal layer is clearly related to the diameter of the needle. In an attempt to decrease the level of pain an individual experiences when receiving an injection, the use of microneedles has been investigated. Microneedles can be fabricated in lengths that enable the dermal barrier to be penetrated sufficiently deep for drug delivery to occur, but not so deep as to stimulate nerves that cause pain and discomfort.
As an alternative to macro-needles, microneedles having a diameter measured in micrometers have been developed. The reduced size decreases discomfort and pain to the patient. Research has demonstrated that silicon microprobes with cross sections on the order of tens of micrometers can penetrate living tissue without causing significant trauma. (K. Najafi, K. D. Wise and T. Mochizuki, xe2x80x9cA High-Yield IC-Compatible Multichannel Recording Array,xe2x80x9d IEEE Micro Trans. on Electron Devices, vol. ED-32, pp. 1206-1211, July 1985.)
Several different types of microneedles have been developed. Glass pipettes have been used to fabricate microneedles with a diameter of approximately 20 xcexcm. These microneedles can be formed by heating a relatively large diameter glass pipette and stretching the pipette until its diameter is reduced to about 20 xcexcm. Glass microneedles of this size can be used to inject and withdraw fluids from a single cell. However, the stretching technique employed to produce the microneedle is rather crude, and it is difficult to accurately and reproducibly control the size of a microneedle fabricated in this manner. Furthermore, such microneedles are extremely fragile.
U.S. Pat. No. 5,457,041 discloses an array of microneedles extending outwardly from a supporting substrate and having tip portions shaped and dimensioned to both carry a biologically active substance and to pierce and penetrate into target cells within tissue, so that the biological substance is transferred from the tip portion and deposited within the target cells. The array of microneedles is fabricated using silicon wafers and photolithographic-based etching techniques. The result is an array of solid microneedles. Any biologically active substance to be delivered by these needles must be loaded onto the tips of the microneedles to effect delivery. Such tip loading is not effective to deliver a precisely metered dose of a biologically active substance. Generally, medical treatment methodologies that include the transdermal injection of drugs into a patient require precisely controlling the amount of drug delivered. Delivery of too little amounts of a drug may not effect the desired result, and too much of the drug can have serious, possibly even fatal, consequences. Therefore, it would be desirable to provide a microneedle-based drug delivery system that offers better control over the dosage of the drug delivered by the microneedles, than this prior art technique.
U.S. Pat. No. 5,591,139 discloses a different type of silicon-based microneedle. Rather than producing an array of needles that extend outwardly from a substrate, this patent discloses fabricating a microneedle that extends parallel to the plane of a silicon substrate. Using a combination of masking and etching techniques, a hollow microneedle is formed, which includes an interface region and a shaft. A shell defining an enclosed channel forms the shaft, which has ports to permit fluid movement. The interface region includes microcircuit elements that can be used to provide micro-heaters, micro-detectors or other micro-devices on the microneedle. While a microneedle incorporating a fluid path is extremely useful, the shaft of the microneedle disclosed in this patent is relatively thin and narrow, and breakage is a concern. Furthermore, incorporation of electronic circuitry in the interface region increases the costs and complexity of these microneedles, and such circuitry is not required for all microneedle applications. Finally, using and manipulating an individual microneedle, as opposed to an array of microneedles, presents other challenges.
A more recent patent directed to microneedle arrays is U.S. Pat. No. 6,033,928, which discloses an array of semiconductor microneedles, each having a diameter sufficiently small to exhibit quantum effects. These semiconductor microneedle arrays can be used to provide a semiconductor apparatus with high information-processing functionality and are fabricated by forming a silicon dioxide film on a silicon substrate. Hemispherical grains made of silicon, each having an extremely small diameter, are then deposited on the film by vapor deposition. After annealing the hemispherical grains, the silicon dioxide film is etched using the hemispherical grains as a first dotted mask, thereby forming a second dotted mask comprising the silicon dioxide film. The resulting second dotted mask is used to etch the silicon substrate to a specified depth, thereby forming an aggregate of semiconductor microneedles. Note that drug delivery applications generally do not require a microneedle that is a semiconductor.
In consideration of the prior art discussed above, it would be desirable to provide an array of microneedles that each incorporate a fluid channel through which a controlled volume of fluid can be delivered. Preferably, such microneedle arrays would be designed to minimize the breakage of individual needles within the array, a common problem with prior art microneedles. It would be desirable to provide a method for fabricating such an array of microneedles that utilizes conventional micro-scale fabrication techniques, such that the size of the microneedles can be accurately and reproducibly controlled. It would be further desirable to provide a microneedle-based drug delivery system that offers full control over the dosage of the drug delivered by the microneedles. The prior art does not disclose or suggest such an apparatus or method.
In accord with the present invention, a hollow microneedle for transcutaneously conveying a fluid is defined. The microneedle has a generally conical-shaped body, with a beveled, non-coring tip that is able to pierce tissue and a broad base. A fluid channel extends through the body connecting the broad base in fluid communication with the tip.
Preferably, the height of the microneedle, which is the distance from the broad base to the tip, is the about the same or substantially less than a width of the broad base. The microneedle is fabricated from a silicon-based substrate, using semiconductor fabrication techniques.
In one embodiment, an array of hollow microneedles are fabricated. The array includes a substrate with at least one inlet and a plurality of outlets in fluid communication with the at least one inlet. The microneedles extend outwardly from the substrate, each being proximate to an outlet through the substrate. Each microneedle in the array is generally configured as noted above.
Another aspect of the present invention is directed to a method of manufacturing a hollow microneedle. The method includes the steps of providing a substrate; forming an orifice within the substrate, such that the orifice passes completely through the substrate; and removing a substantial portion of the substrate, leaving a remainder. The remainder is disposed around the orifice and is generally conical in shape, so that the orifice is disposed generally along a central axis of the conical shape. The step of removing a substantial portion of the substrate preferably bevels a tip of the conical shape.
In a preferred method, the substrate is silicon or polysilicon, and conventional semiconductor fabrication methods are employed for the fabrication process. For example, to form an orifice, a first mask is formed such that only portions of the substrate corresponding to a desired location of the orifice are exposed. The orifice is then etched, and the first mask removed. A second mask is formed and a nitride layer is deposited on unmasked areas. The second mask is then removed, and the substrate is etched to remove a substantial portion. The step of etching the substrate preferably comprises the step of performing an anisotropic etch, and then performing an isotropic etch.
Another aspect of the present invention is directed toward a method of manufacturing an array of hollow microneedles, which is generally consistent with the method discussed above.
Yet another aspect of the present invention is directed to a minimally invasive diagnostic system for sampling and analyzing a biological fluid from a patient. Such a system includes a handheld diagnostic unit, a disposable cartridge for obtaining a sample of the biological fluid, and a sensor that when in contact with the sample, produces a signal indicative of a characteristic of the biological fluid. The handheld diagnostic unit includes a housing, a processor, a display electrically coupled to the processor, a keypad electrically coupled to the processor, and a memory electrically coupled to the processor. The disposable cartridge includes a housing and an array of microneedles and is adapted to bring the sample into contact with the sensor.
Preferably, the memory stores machine instructions that when executed by the processor, cause it to perform a diagnostic procedure and indicate a result of the diagnostic procedure to a user on the display. In one embodiment, the diagnostic procedure determines a level of glucose in the biological fluid. Preferably, the housing includes a receptacle having a size and shape adapted to receive the disposable cartridge, such that when the cartridge is inserted into the receptacle, the sample of biological fluid is brought into contact with the sensor, and the sensor is electrically connected to the processor. In one embodiment, the sensor is disposed in the disposable cartridge, while in another embodiment, the sensor is disposed in the housing of the handheld diagnostic unit.
A still further aspect of the present invention is directed toward a minimally invasive drug delivery system for infusing a medicinal fluid into a patient. This system includes a handheld control unit, a disposable cartridge for delivering the medicinal fluid to the patient, and a fluid line connecting the handheld unit to the disposable cartridge. The handheld unit includes a housing, a processor, a display electrically connected to the processor, a keypad electrically connected to the processor, a memory electrically connected to the processor, a medicinal fluid reservoir controllably connected to the processor, a medicinal fluid outlet in fluid communication with the medicinal fluid reservoir, and an actuator that develops a pressure to force the medicinal fluid through the medicinal fluid outlet so that it is infused into a patient. The disposable cartridge includes a housing and an array of microneedles through which the medicinal fluid is infused into the patient.